Development of New Method for Construction of Chiral, Non-Racemic Quaternary Carbon Center by Enzymatic Acylation of Alcohols and Application Thereof

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Construction of chiral, non-racemic quaternary carbon center via enzymatic acylation of alcohols is believed to be an effective environmentally benign process because of its high enantioselectiviry and safe and easy operation; however, the successful examples have been limited. This is mainly due to the problems of the currently-best method using vinyl esters, which involve inactivation of the enzymes and easy racemication via intramolecular acyl group migration. Recently, we have disclosed their resolution by using 1-ethoxyvinyl esters (EVEs), leading to the discovery of the first effective enzymatic desymmetrization of symmetric diols and the first domino asymmetric reactions. This project has aimed at the expansion of these methods for the construction of chiral, non-racemic quaternary carbon centers and also their application for asymmetric synthesis of leading compounds for new drug discovery. The followings are summary of the results:1. The enzymatic desymmetrization method was e … More ffective for wide range of 1,2- and 1,3-diols, and a new general method for the construcntion of chiral, non-racemic quaternary carbon centers has been established. This protocol was successfully applied for asymmetric synthesis of either enantiomer of the ABCDE-analog of antitumor antibiotic fredericamycin A and also for asymmetric preparation of the various oxindoles (86- 98% ee) with a chiral, non-racemic quaternary carbon center at the C-3 position and a variety of N-1 protective group.2. The lipase-catalyzed domino asymmetric synthesis was applied to various furfuryl alcohol to provide a one-pot synthesis of 7-oxabicycloheptenes (91- 99% ee) with a chiral quaternary carbon center. Especially, useful chiral synthons bearing a vinyl bromide moiety were prepared from the 3-bromofurfuryl alcohols. The first domino process involving dynamic kinetic resolution was achieved by the similar reaction of α-hydroxynitrones to give aza-polycyclic products in good yields. The asymmetric total synthesis of a natural pyrrolizidine alkaloid, rosmarinecine, was attained in 3 steps from a readily available racemic hydroxynitrone and a maleic acid. Less